Ammonium Chloride → Tert-butyl 3-(3-chloro-2-fluorophenyl)-3-hydroxypyrrolidine-1-carboxylate

HRID 1931878Notes

Reaction equation

HRID 1931878 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9].C([Li])CCC.[C:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:4]1[C:3]([F:9])=[C:2]([C:24]2([OH:27])[CH2:25][CH2:26][N:22]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:23]2)[CH:7]=[CH:6][CH:5]=1

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 471360Tert-butyl 3-oxopyrrolidine-1-carboxylateHCID 36857621-Bromo-3-chloro-2-fluorobenzeneHCID 178418339Butyllithium

Product 1

HCID 67404349Tert-butyl 3-(3-chloro-2-fluorophenyl)-3-hydroxypyrrolidine-1-carboxylateYield 58.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 1-bromo-3-chloro-2-fluorobenzene (5.0 g, 23.8 mmol) in dry tetrahydrofuran (50 mL) under nitrogen at −78° C., was added dropwise n-butyllithium (2.5 M in tetrahydrofuran, 9.5 mL, 23.8 mmol). The mixture was stirred for 0.5 h at −78° C. after which a solution of 1-N-boc-3-pyrrolidinone (4.37 g, 23.8 mmol) in dry tetrahydrofuran (20 mL) was added drop wise. The resulting mixture was brought to ambient temperature, aqueous saturated ammonium chloride (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phase was dried (MgSO4), filtered and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate/methanol, 4:1 to 1:1) gave the title compound (4.42 g). MS m/z (rel. intensity, 70 eV) 315 (M+, 1), 259 (16), 214 (31), 157 (17), 57 (bp).

Workup

  1. additionwas added drop wise
  2. customwas brought to ambient temperature
  3. extractionthe mixture was extracted with ethyl acetate (3×50 mL)
  4. dry with materialThe combined organic phase was dried (MgSO4)
  5. filtrationfiltered
  6. customevaporated
  7. customPurification by flash column chromatography on silica gel (ethyl acetate/methanol, 4:1 to 1:1)

Sources & evidence

ORD record
ord-31b003cb996a48aaaa63f998e4bfb427
Source dataset
uspto-grants-2012_05
Patent number
US08188301B2

Reaction notes

Loading…